Method for the treatment of



United States Patent 25,502 METHOD FOR THE TREATMENT OF CLONIC TYPESEIZURES Edwin J. de Beer, deceased, late of Tuckahoe, N.Y., by

Helen I. de Beer, executrix, Tuckahoe, N.Y.; said Erlwin J. de Beerassignor to Burroughs Wellcome & Co. (U.S.A.) Inc., Tuckahoe, N.Y., acorporation of New York No Drawing. Original No. 2,955,073, dated Oct.4, 1960, Ser. No. 738,982, June 2, 1958. Application for reissue Sept.20, 1962, Ser. No. 225,961

4 Claims. (Cl. 167-65) Matter enclosed in heavy brackets appears in theoriginal patent but forms no part of this reissue specification; matterprinted in italics indicates the additions made by reissue.

This invention relates to a preparation for the alleviation of clonictype seizures such as febrile convulsions.

This condition occurs frequently and is especially a matter of concernin children. In susceptible individuals a rise in body temperature tolevels of about 101 F. or somewhat higher is attended by severeconvulsive seizures. The convulsive movements may cause bodily injury,severe cardiovascular damage, or even death. It is believed that thesefebrile convulsions are closely related to epileptic seizures and that adamage resulting fro-m febrile convulsions in childhood predisposestoward epilepsy in later life.

Treatments available at the present time are unsatisfactory, often beinginadequate to control the convulsions and difficult to apply. One methodfrequently used is to cool the patient by means of ice packs. Anothermethod is to place the patient under heavy sedation by means ofanesthetic barbiturates until loss of consciousness is approached.Hospitalization is frequently required. Certain anticonvulsants, such asdiphenylhydantoin may actually exacerbate the seizures.

The ideal drug for use against febrile convulsions should not onlydiminish sensitivity to these seizures but should have antipyreticaction. Since many barbituric acids derivatives are antipyretics anumber of these were examined. Two test procedures were employed. Themore fundamentals of these involves a study of the action of drugsagainst spasms resulting from artificial fever in mice. Since, however,there is experimental correlation between drugs eifective againstepilepsy and those effective against metrazol-produced spasms, theprimary screen was against metrazol spasms.

Method: Experimental seizures were induced in animals by means ofpentylenetetrazol (metrazol) and the new compounds were tested for theirability to prevent al seizure activity. Metrazol was employed since theseizures produced are mainly clonic in pattern and drugs effectiveagainst such experimental seizures have been found to show some activityclinically in the treatment of petit mal and other minor convulsivedisorders.

In the preliminary screening test, doses of 10, 100, and 600 rug/kg. ofeach drug were administered orally to groups of mice, and anticonvulsantactivity was tested at 1, 2, and 3 hours after dosing. Any signs oftoxicity, such as depression and incoordination, were noted.

Results: The anticonvulsant potency and toxicity of each new drug wasexpressed as the percentage of animals protected from the seizure andthe percentage showing toxicity, within the dose range of 10 to 600mg./kg.

Results were as follows:

Percentage otanimals protected against, metmzol seizure PercentageShowing Toxicity B.W. Compound Number Derivative N-PlienylbdrbilulN-lhenylneonfil N-ololyib:trbilril N-m-Tolylbarbital.

These results show that N-phenylbarbital (B.W. No. 40l) is unique inthis series of N-substituted barbitals, as a compound with markedactivity against metrazolinduced clonic seizures.

In further detailed testing, the following results were obtained:

The protective index, or ratio of the toxic to the effective dose, of4.2 was higher than that of phenobarbital, trimethadione, andmetharbital, and accordingly indicates a higher degree of safety.

It will be observed that of the above series of barbituric acidderivatives tested, N-phenylbarbital had a unique action different fromthat of even very close relatives (note Nos. 4024). Accordingly the morefundamental test procedure was applied to this compound in comparisonwith drugs of known properties.

Febrile seizures were induced in mice by means of a microwave diathermygenerator. In animals between 3 and 4 weeks of age, a generalizedseizure response was obtained when the body temperature was raised to F.The threshold convulsive temperature was independent of the rate oftemperature rise. The pattern of febrile seizure was principally clonictype. A tonic component observed at higher temperatures was mild,spasmodic, and unsustained. Drugs were tested for their ability (1) tomodify the threshold convulsive temperature (2) to abolish the seizurecompletely and (3) to retard the rate of rise in body temperature in thepresence of hyperthermic stimulus.

As shown below, trimethadione, meprobamate and phenobarbital, of valuein the treatment of petit mal and myoclonic epilepsies, were eflectivein the control of febrile seizures, but large and toxic doses wererequired to abolish the clonus completely. Such drugs are also effectiveagainst the clonic metrazol-induced seizure. Diphenylhydantoin, which isineffective against experimental metrazol seizures, and in petit mal andis used primarily for treatment of tonic major seizures, failed tocontrol the febrile convulsion and indeed, exacerbated the clonicpattern. Acetazolamide raised the threshold convulsive temperature butdid not abolish clonus completely; it was also inactive againstmetrazol-induced seizures.

N-phenylbarbital proved remarkably effective against both metrazol andfever-induced seizures. In addition. it was strongly antipyretic and itsaction was relatively rapid on oral administration. Compared withphenobarbital and metharbital, its toxicity was low and its protectivetheraupeutic index (ratio of toxic to effective dose) was high.

The compound has the additional advantage of being free from toxicsideefifects at doses which elfectively protect against febrileconvulsions. The Side-effects which often may be observed with othercompounds may be detected by the following tests: (1) the rightingreflex test, (2) the positional sense test, (3) the gait stance test.(4) the muscle tone test, and (5) the equilibrium test. Graded oraldoses gave a TD of 190 lug/kg. for these neural toxicity tests. Thelethal action of B.W. 401 required much higher doses. The LD was foundto be 900 mg./kg.

For treatment of febrile convulsions in humans the required dose levelis of the order of 3 to 5 mg./kg. three times a day. Roughly, 5()100 mg.in each dose Would be given to children and about twice as much toadults. The drug may be presented in capsules, tablets or in the form ofan elixir or syrup. The latter is of particular convenience in treatingyoung children.

EXAMPLE 1 Five hundred and thirty g. of N-phenylbarbital is groundthoroughly and sifted through a 60 mesh sieve. It is then mixed with116.6 g. of dried potato starch and again passed through a 60 meshsieve. The powder is then granulated twice each time with 80 cc. ofpercent *Feculose" solution. Feculose is the tradename of a partiallydegraded starch preparation consisting largely of starch andhigh-molecular dextrins. The granules are dried overnight at 110 F. andbroken up so as to pass through a 24 mesh sieve. To this was added amixture passed through a mesh sieve of 13.25 g. of dried potato starchand 7.95 g. of stearic acid. The whole was mixed thoroughly and fed intoa tabletting machine using No. 74 scored punches. The tablets soprepared Weigh 139.5 mg. and contain each mg. of drug.

EXAMPLE 2 Ten g. of N-phenylbarbital is dissolved in 200 cc. of U.S.P.alcohol and to this is added with stirring 200 cc. each of glycerine,propylene glycol and polyethylene glycol 400. A few cc. of lemon extractis then added and the solution is made up to 1 liter with water.

EXAMPLE 3 Ten g. of N-phenylbarbital is dissolved in 350 cc. of U.S.P.alcohol and to this is added cc. of glycerine, 300 cc. of propyleneglycol and 100 cc. of 80% cane syrup (U.S.R.). A few cc. of lemonextract are then added and the solution is made up to 1 liter withwater.

What 1 claim is:

1. A method for the treatment of febrile convulsions which comprises theadministration of N-phenylbarbital.

2. A method for the treatment of febrile convulsions which comprises theadministration of 35 rng/kg. of N-phenylbarbital.

3. A method for the treatment of (Ionic type Seizures which comprisesthe administration of N-phenylharbl'tal to a patient suffering from thiscondition.

4. A method as set fort/1 in claim 3, in which the clom'c seizure isperil ma].

References Cited in the file of this patent or the original patent.

Bush: J. Pharmacol.. vol. 68, 1940, pp. 278283 (thru Che'm. Abst., vol.34, 2458).

Hjort: J. PharmacoL, vol. 35, 1929, pp. 164 (thru Chem. Abst. 23, 3024).

Cecil: Textbook of Medicine, 7th ed., 1948, p. 28, \V. B. Saunders Co.

Cecil: Textbook of Medicine, 9th ed. 1955, pp. 1486 1487.

Williams: Detoxication Mechanisms, 1947, pp. 219- 220, John Wiley andSons, Inc., NY.

Irwin: J. P'harm. Exptl. Then, July 1958, pp. 206211.

Daly: Staff Meeting Mayo Clinic, May 15, 1957, vol. 32, No. 10, p. 260.

